Live attenuated vaccines prepared from simian immunodeficiency virus (SIV) have provided the best protective immunity in challenge experiments. SIV provides a model system to investigate the mechanisms of eliciting protective immunity for AIDS vaccines. In animals vaccinated with attenuated SIV, immune responses may be elicited due to continuous expression of native SIV proteins and/or antigen presentation in the native replication site of the virus. Thus, vaccinated animals can elicit protective immunity and be protected from challenging with pathogenic virus. However, the mechanisms of eliciting protective immunity are unclear, and the use of live replication-competent HIV raises safety concerns in human trials. To address the safety concerns of replication-competent HIV vaccines, the investigators have developed a replication-defective SIV. This proposal describes experiments to investigate the mechanisms that elicit cellular immune responses in animals vaccinated with replication-defective SIV. First, the investigators will examine whether SIV protein expressed in the endogenous pathway is critical to elicit immune responses (cellular or humoral or both). Cell-mediated immune responses have been suggested as important immunological correlates to protective immunity. However, the specific viral proteins contributing to protective immunity are currently unknown. Viral factors contributing to the immune response also will be examined. Second, to contribute to the safety of vaccines, the applicants will investigate the replication competency of defective SIV preparations in the vaccinated animals. Third, the applicants will investigate the immune responses contributing to protective immunity in vaccinated animals. The data obtained may provide vital information for developing a safe and effective HIV prophylactic vaccine for humans.